US3455925A - Process for preparing o,s-bis(alkoxycarbonyl)thiamine derivatives - Google Patents

Process for preparing o,s-bis(alkoxycarbonyl)thiamine derivatives Download PDF

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US3455925A
US3455925A US555897A US3455925DA US3455925A US 3455925 A US3455925 A US 3455925A US 555897 A US555897 A US 555897A US 3455925D A US3455925D A US 3455925DA US 3455925 A US3455925 A US 3455925A
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thiamine
bis
reaction
parts
chloroform
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Shinzaburo Sumimoto
Kanji Tokuyama
Manabu Fujimoto
Takashi Maeda
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Shionogi and Co Ltd
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Shionogi and Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D415/00—Heterocyclic compounds containing the thiamine skeleton

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  • Free DCBT DCBTJ'IGI'H 0 (0801 extract) (@301; extract Q bwwn-ucl ran-cu H Tri-CBT -DCBT --CET Reaction of diothyl pyrocarbonato in 0110 lisp.
  • the present invention relates to a process for preparing bis(alkoxycarbonyl)thiamine derivatives. More particularly, it relates to an improvement in the production of O,S-bis(alkoxycarbonyl)thiamine and non-toxic salts thereof which are useful as the long-acting vitamin B agents.
  • O,S-diacy1thiamine derivatives can be prepared by reacting an acid salt of thiamine with carboxylic acid anhydride or carboxylic acid halide at non-acidic pH [U.S. Patent No. 2,752,348].
  • the O,S-bis(alkoxycarbonyDthiamine derivatives have been prepared by several methods, for instance, by reacting an S-alkali salt of thiol type thiamine with alkyl halogenocarbonate in the presence of a basic catalyst (e.g. triethylamine or sodium alkoxide) (hereinafter referred to as halogenocarbonate method) [c.g. Chemical & Pharmaceutical Bulletin, vol. 10, pp.
  • a basic catalyst e.g. triethylamine or sodium alkoxide
  • bis(alkoxycarbonyhthiamine can be prepared in a quantltative yield by employment of 2.0 to 2.4 mol equivalent of pyrocarbonic acid diester in two steps to an aqueous solut1on of S-alkali metal salts of thiol type thiamine under cooling below room temperature and by the addition of 1.0 to 1.2 mol equivalent of alkali hydroxide in the latter step of the reaction.
  • the process of the present invention comprises reacting an S-alkali metal salt of a thiol type thiamine with 1.0 to 1.2 mol equivalent of a pyrocarbonic acid diester represented by the general formula:
  • M represents an alkali metal (e.g. potassium, sodium or lithium) and R represents an alkyl group having one to five carbon atoms.
  • alkali metal salt of thiol type thiamine of the Formula I may be prepared by reacting a salt of thiamine (e.g. thiamine chloride hydrochloride, thiamine mononitrate, thiamine monothiocyanate, thiamine monophosphoric acid salt, thiamine mononaphthalene-1,5-disulfonic acid salt or thiamine monosulfate) with alkali metal hydroxide (e.g. potassium hydroxide, sodium hydroxide or lithium hydroxide) according to the conventional manner.
  • a salt of thiamine e.g. thiamine chloride hydrochloride, thiamine mononitrate, thiamine monothiocyanate, thiamine monophosphoric acid salt, thiamine mononaphthalene-1,5-disulfonic acid salt or thiamine monosulfate
  • alkali metal hydroxide e.g. potassium hydroxide, sodium hydroxide or lithium hydroxide
  • S-sodium salt of thiol type thiamine is prepared by reacting thiamine chloride hydrochloride with 3.0 mol equivalent of sodium hydroxide in water and also prepared by reacting thiamine mononitrate with 2.0 mol equivalent of sodium hydroxide in water.
  • This preparation of the starting material may be ordinarily eifected in the range of temperature from 5 to 25 C.
  • O,S-bis(alkoxycarbonyl)thiamine of the formula (IV) are illustrated independently in the following passages, these may usually be carried out subsequently to the preparations of the starting alkali salt of thiol type thiamine.
  • the pyrocarbonic acid diester adopted as an alkoxycarbonylating agent in the present process is a diester of pyrocarbonic acid COOH o 0 OH the industrial process for preparing this ester has been investigated since 1960 and it has been known that this reagent reacts with an organic compound having an active hydrogen atom such as thiol group and amino group in an amino acid [Bull Soc. Chim. France, 1965, pp. 3 82 to 385]. Accordingly, pyrocarbonic acid diether is such a reagent as exhibits the powerful reactivity as an alkoxycar-bonylating agent.
  • the said pyrocarbonic acid diester can be readily prepared at a low cost such as by reacting an alkali salt of monoalkyl carbonate with alkyl halogenocarbonate and this reaction is represented by the following formulae:
  • the starting S-alkali salt of thiol type thiamine of the Formula I is first allowed to react with 1.0 to 1.2 mol equivalent of the pyrocarbonic acid diester.
  • the reaction may be effected under cooling below room temperature, that is, 25 C.
  • the present process can be effected with or without isolation of the S-alkoxycarbonylthiamine, but it is commercially more advantageous to efiect the reaction without isolation of the S-alkoxycarbonylthiamine in view of high yield, rapid reaction time and small amount of solvent required.
  • the second step after treatment of the S-alkoxycarbonylthiamine with 1.0 to 1.2 mol equivalent of alkali hydroxide, the result mixture is then subjected to a treatment with 1.0 to 1.2 mol equivalent of the pyrocarbonic acid diester.
  • the reaction may proceed under cooling below room temperature, that is, 25 C.
  • step by step these steps may be effected successively without isolation of the intermediary compounds such as S-alkoxycarbonylthiamine or O-alkoxycarbonylthiamine. Further, this reaction can be performed batchwise or continuously.
  • alent of pyrocarbonic acid diester in successive two steps to an aqueous solution of S-alkali metal salt of thio type thiamine under cooling and by the previous addition of 1.0 to 1.2 mol equivalent of alkali hydroxide in the latter step of the reaction.
  • results obtained by the thin layer chromatographic analysis (hereinafter referred to as TLC) in the production of O,S-bis(ethoxycarbonyl)thiamine (hereinafter referred to as DCET) by the present process will be shown in FIGURES 1 to 13 of the attached drawings together with those results obtained by employment of ethyl chlorocarbonate according to the known method and those of diethyl pyrocarbonate in one step for the purpose of illustrating how does the present process hold a unique advantage over the prior art.
  • TLC thin layer chromatographic analysis
  • DCET O,S-bis(ethoxycarbonyl)thiamine
  • Thickness of plate 300;.
  • Amount of samples 1 to 10 ,ul. of a 0.1 to 5.0% solution.
  • Developing solvent a mixture of chloroform and acetone (1:2 in volume).
  • Coloring agent Dragendorif reagent.
  • FIGURE 1 shows the chromatogram in TLC of the extract obtained by shaking the reaction mixture with chloroform in the state of free S-ethoxycarbonylthiamine (hereinafter referred to as CET) in the present reaction.
  • FIGURE 2 shows the chromatogram in TLC of an authentic sample of CET.
  • FIGURE 3 shows the chromatogram in TLC of the chloroform layer obtained by shaking the reaction mix ture with chloroform in the state of free DCET in the present reaction.
  • FIGURE 4 shows the chromatogram in TLC of the aqueous solution after extraction of free DCET with chloroform in the present reaction.
  • FIGURE 5 shows the chromatogram in TLC of the DCET-HCI chloroform layer obtained by shaking the free DCET chloroform layer with 15% hydrochloric acid in the present reaction.
  • FIGURE 6 shows the chromatogram in TLC of the aqueous solution after extraction of DCET-HCI with 3 chloroform in the present reaction.
  • FIGURE 8 shows the chromatogram in TLC of the ethyl acetate washings after treatment of DCET-HCl-H o with ethyl acetate in the present reaction.
  • FIGURE 9 shows the chromatogram in TLC of DCET-HCl-H O after recrystallization from acetone in the present reaction.
  • FIGURE 10 shows the chromatogram in TLC of the extract obtained by Shaking the reaction mixture with chloroform in the state of free DCET in the reaction of S-sodium salt of thiamine with ethyl chlorocarbonate according to the method described in [Chemical & Pharmaceutical Bulletin, vol. 10, pp. 1107 to 1113 (1962)].
  • FIGURE 11 shows the chromatogram in TLC of the DCET-HC1'H O chloroform layer obtained by shaking the chloroform layer with HCl in the reaction of FIGURE 10.
  • FIGURE 12 shows the chromatogram in TLC of the extract obtained by shaking the reaction mixture with chloroform in the state of free DCET in the reaction of thiamine mononitrate with diethyl pyrocarbonate in one step.
  • FIGURE 13 shows the chromatogram in TLC of the DCET-HCl-H O chloroform layer obtained by shaking the free DCET chloroform layer with 15% hydrochloric acid in the reaction of FIGURE 12.
  • the DCET can be prepared in a high purity With a small amount of side product which may be readily removed as is clearly understood by the drawing.
  • O,N,S-tri(alkoxycarbonyl)thiamine and a compound which may be assumed as O,N,N,S-tetra(alkoxycarbonyDthiamine may be liable to be side-produced depending upon the reaction conditions employed, and these side-products can be removed simply by a conventional purifying manner such as recrystallization or washing with a suitable solvent (e.g. ethyl acetate).
  • a suitable solvent e.g. ethyl acetate
  • the present process shows a conspicuous advance of yield in comparison with those of the known methods. For instance, although only about 45% of crude yield is achieved in the prior halogenocarbonate method, more than 95% of crude yield (purity: 94.9 to 95.3%) can be established in the present process.
  • addition of the reagent can be effected at a time and it does not require a dropwise manner. Further, the reaction rate is so rapid that the time required for the reaction and post treatment will be much shortened in comparison to any of those of the known halogenocarbonate method.
  • O,S-bis(alkoxycarbonyl)thiamine derivatives and non-toxic salts thereof are useful as socalled long-acting vitamin B agents. It is noted that, when orally administered, these compounds are rapidly absorbed from the intestinal canal and can maintain a high concentration of vitamin B in the blood for a long time.
  • Example 1 Into a four-necked flask (500 parts by volume) equipped with a stirrer, a thermometer and a dropping funnel, there are added thiamine mononitrate (32.74 parts by weight) and 5% sodium hydroxide solution (168.0 parts by weight) under stirring and the resultant mixture is stirred at 20 to 21 C. for 1.5 to 2.0 hours for opening the thiazolium ring to prepare S-sodium salt of thiol type thiamine.
  • thiamine mononitrate 32.74 parts by weight
  • sodium hydroxide solution 168.0 parts by weight
  • the reaction mixture is shaken with chloroform (150 parts by volume) and then with the additional amount parts by volume) of chloroform successively, and in each case the formed aqueous layers are discarded after the absence of O,S-bis (ethoxycarbonyl) thiamine is confirmed by the thin layer chromatography.
  • the chloroform layers are then combined and shaken well with 15 hydrochloric acid (36.48 parts by weight) for formation of the hydrochloride.
  • the acidic aqueous layer is salted out with sodium hydrochloride and shaken with chloroform (30 parts by volume). The latter chloroform layer is combined with the former chloroform layer.
  • the chloroform layer is dried over anhydrous sodium sulfate and the chloroform is evaporated at 50 to 60 C. under reduced pressure. The residue is transmitted into an open vessel and the residual solvent is evaporated gradually at room temperature. After being allowed to stand at room temperature overnight, the obtained substance on the vessel is moistened and converted into crystalline hydrate, which is then dried under reduced pressure to give O,S-bis(ethoxycarbonyl) thiamine hydrochloride monohydrate (45.78 to 46.22 parts :by weight) as crystals melting at 112.5 to 119.5 C. Crude yield: 95.18 to 96.09%. Purity: 94.9 to 95.3%. This substance is proved to be almost pure substance by the coloring test with Dragendorff reagent or conc.
  • the said crude crystals are treated with ethyl acetate (170 parts by volume) to give 99.2 to 100.7% purity of crystals (42.49 to 43.03 parts by weight) melting at 119 to 119.5 C.
  • This substance shows a single spot of 0,5- bis(ethoxycarbonyl) thiamine hydrochloride monohydrate in the thin layer chromatography, and no other spot such as O,N,S-tri(ethoxycarbonyl)thiamine or O,N,N,S- tetra(ethoxycarbonyl)thiamine is observed.
  • This chromatogram is shown in FIGURE 7.
  • This substance is recrystallized from acetone for arranging the shape of crystals to give colorless prisms melting at 121 to 123 C. (decomp.).
  • the chromatogram of the prisms shows a single spot of O,S-bis(ethoxycarbonyl)thiamine hydrochloride monohydrate in the thin layer chromatography, as shown in FIGURE 9.
  • Example 2 To a solution of thiamine chloride hydrochloride (33.7 parts by weight) in Water (44 parts by volume), there is added 10% sodium hydroxide (124.0 parts by weight), and the resultant mixture is stirred at 20 to 21 C. for 2 hours. Under cooling at to 2 C. and with stirring, the mixture is combined with diethyl pyrocarbonate (17.82 parts by weight) and the resultant mixture is stirred at 0 to 2 C. for an hour. Further, there are added sodium hydroxide (96.0 parts by weight) and then diethyl pyrocarbonate (17.82 parts by weight), and the resultant mixture is stirred at 0 to 2 C. for 2 hours. The reaction mixture is treated in the same manner as in Example 1 to give O,S-bis (ethoxycarbonyl)thiamine hydrochloride monohydrate (42.90 parts by weight).
  • Example 3 S-sodium salt of thiol type thiamine dihydrate is allowed to react with dimethyl pyrocarbonate (B.P. 46 C./ 5 mm. Hg, d3" 1.2585, n 1.3950) in the same manner as in Example 1 to give O,S-bis(methoxycarbonyl)thiamine as colorless plates melting at 139 (decomp.).
  • dimethyl pyrocarbonate B.P. 46 C./ 5 mm. Hg, d3" 1.2585, n 1.3950
  • Example 5 Into a four-necked flask (500 parts by volume) equipped with a stirrer, a thermometer and a dropping funnel, there are added thiamine mononitrate (32.74 parts by weight) reaction mixture. The resultant mixture is stirred at l to 1 C. for 2 hours to precipitate S-ethoxycarbonylthiamine as crystals.
  • the reaction mixture is shaken with chloroform (150 parts by volume) and then with the additional amount parts by volume) of chloroform.
  • the chloroform layers are combined, and become gelatinous gradually.
  • the gelatinous substance is collected by filtration and washed sufiiciently with 99% ethanol (about 100 parts by volume) for the separation of the insoluble part (thiamine mononitrate) (0.65 parts by Weight) from the ethanolic solution.
  • the ethanolic solution is combined with the chloroform layer, and the mixture is dried over anhydrous sodium sulfate.
  • the solvent is evaporated under reduced pressure at 50 to 60 C. on a water both to give S-ethoxycarbonylthiamine (34.11 parts by weight) as crystals melting at 134.0 to 134.5 C. (decomp.). Yield: 96.25%. Purity: 9 6.7%.
  • Process for preparing O,S-bis(ethoxycarbonyDthiamine derivatives which comprises reacting an S-alkali metal salt of thiol type thiamine with 1.0 to 1.2 mo1equivalent of diethyl pyrocarbonate in an aqueous medium under cooling below room temperature to give S-ethoxycarbonylthiamine and reacting the S-ethoxycarbonylthiamine with 1.0 to 1.2 mol equivalent of diethyl pyrocarbonate in the presence of 1.0 to 1.2 mol equivalent of alkali hydroxide in an aqueous medium under cooling below room temperature.

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US555897A 1965-09-30 1966-06-07 Process for preparing o,s-bis(alkoxycarbonyl)thiamine derivatives Expired - Lifetime US3455925A (en)

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AT (1) AT264727B (enrdf_load_stackoverflow)
CH (1) CH479620A (enrdf_load_stackoverflow)
DK (1) DK116131B (enrdf_load_stackoverflow)
ES (1) ES321261A1 (enrdf_load_stackoverflow)
FR (1) FR1474790A (enrdf_load_stackoverflow)
GB (1) GB1072834A (enrdf_load_stackoverflow)
IL (1) IL25047A (enrdf_load_stackoverflow)
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CA690732A (en) * 1964-07-14 Takamizawa Akira Thiamine derivatives and production thereof

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CA690732A (en) * 1964-07-14 Takamizawa Akira Thiamine derivatives and production thereof

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IL25047A (en) 1969-11-30
DK116131B (da) 1969-12-15
DE1620350A1 (de) 1970-03-12
AT264727B (de) 1968-09-10
NL6604969A (enrdf_load_stackoverflow) 1967-03-31
DE1620350B2 (de) 1973-01-04
NO122595B (enrdf_load_stackoverflow) 1971-07-19
CH479620A (de) 1969-10-15
ES321261A1 (es) 1966-11-01
GB1072834A (en) 1967-06-21
FR1474790A (fr) 1967-03-31

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